Mechanisms of microbiome-driven cardiac allograft outcomes

微生物组驱动的同种异体心脏移植结果的机制

• 批准号: 10621899
• 负责人: Jonathan S Bromberg
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-13 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621899
• 关键词: Address; Alloantigen; Allografting; Anaerobic Bacteria; Anti-Inflammatory Agents; Antibiotics; Atherosclerosis; Automobile Driving; B-Lymphocytes; Bacteria; Bacteroides; Bifidobacterium; Bile Acids; Blood; Cardiac; Cells; Characteristics; Chronic; Communities; Complex; Congestive Heart Failure; Data; Dendritic Cells; Desulfovibrio; Diagnosis; Diagnostic; Drug Exposure; Endothelial Cells; Endotoxins; Epithelium; Equilibrium; Fiber; Fibrosis; Functional disorder; Goals; Graft Rejection; Graft Survival; Health; Heart Transplantation; Immune; Immune response; Immunity; Immunologics; Immunosuppression; Immunosuppressive Agents; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Intestines; Knowledge; Lactobacillus; Laminin; Lead; Ligands; Lymphatic; Macrophage; Mediating; Mesentery; Metabolic; Metagenomics; Mission; Molecular; Mucous Membrane; Mus; Myeloid Cells; National Institute of Allergy and Infectious Disease; Outcome; Pathologic; Permeability; Pharmaceutical Preparations; Play; Preventive; Quality of life; Regulatory T-Lymphocyte; Reticular Cell; Role; Serum; Structure; Survival Rate; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Transplantation; Vascular Diseases; Volatile Fatty Acids; Work; acylcarnitine; cell motility; cell type; clinically relevant; cytokine; dysbiosis; fatty acid metabolism; fecal microbiota; graft failure; gut microbiome; heart allograft; immunoregulation; improved; interstitial; intestinal barrier; intestinal epithelium; intestinal injury; isoimmunity; liver injury; lymph nodes; microbial; microbial community; microbiome; mortality; mouse model; novel; permissiveness; post-transplant; pregnant; response; single nucleus RNA-sequencing; systemic inflammatory response; tool; transcriptomic profiling; transplant model; trimethyloxamine

PROJECT SUMMARY Though the one-year survival rate in cardiac transplantation has reached 90-95%, the mortality rate beyond the first year has not changed in the last two decades. Immune-mediated damage remains the primary cause of long-term graft failure. Findings from our and other studies provide the rationale for investigating the gut microbiome as a determinant of post-transplantation outcomes and as a potential tool to induce immune modulation to improve long-term graft outcomes. The goal of this study is to determine the mechanisms by which the gut microbiome impacts allograft outcome. We postulate that the disrupted metabolic activities of the gut microbiome lead to inflammatory responses and intestinal injury via cell-type specific responses in the intestinal cells network, which subsequently modulate alloimmunity and ultimately chronic cardiac graft outcomes. We will take advantage of our clinically-relevant cardiac transplant murine model of chronic rejection with well-characterized alloresponses, induced by pro- or anti-inflammatory bacteria, to determine the alterations in the microbial metabolic activities in Aim 1, then to identify local intestinal barrier changes and the underlying intestinal cell-type specific responses in Aim 2, and finally to characterize systemic alloresponses and graft survival in Aim 3, in order to obtain a holistic understanding of the precise mechanisms of microbiome-driven chronic graft outcomes. The proposed work will identify novel and critical microbiome-based targets for diagnostic application and therapeutic intervention, and discern the complex and bidirectional dialogue between the microbiome and alloimmunity to promote transplant immunologic quiescence and long- term cardiac graft survival.

项目概要 虽然心脏移植的一年生存率已达到90-95%，但死亡率却超过了10%。 第一年在过去二十年里没有改变。免疫介导的损伤仍然是导致疾病的主要原因 长期移植失败。我们和其他研究的结果为研究肠道提供了基本原理 微生物组作为移植后结果的决定因素和诱导免疫的潜在工具 调节以改善长期移植结果。本研究的目的是通过以下方式确定机制： 肠道微生物组影响同种异体移植的结果。我们假设代谢活动被破坏 肠道微生物群通过细胞类型特异性反应导致炎症反应和肠道损伤 肠细胞网络，随后调节同种免疫并最终调节慢性心脏移植 结果。我们将利用我们临床相关的慢性排斥反应的心脏移植小鼠模型 具有明确的同种异体反应，由促炎或抗炎细菌诱导，以确定 目标 1 中微生物代谢活动的变化，然后确定局部肠道屏障的变化和 目标 2 中潜在的肠道细胞类型特异性反应，并最终表征全身同种反应 和目标 3 中的移植物存活，以获得对精确机制的全面了解 微生物组驱动的慢性移植物结果。拟议的工作将确定基于微生物组的新颖且关键的 诊断应用和治疗干预的目标，并辨别复杂和双向的 微生物组和同种免疫之间的对话，以促进移植免疫静止和长期免疫 心脏移植物的足月存活率。